Safety, Tolerability, and Pharmacokinetics of Intravenous Doses of PF-07304814, a Phosphate Prodrug Protease Inhibitor for the Treatment of SARS-CoV-2, in Healthy Adult Participants.

Studies on targeted antivirals for treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the ongoing pandemic, are limited. PF-07304814 (lufotrelvir) is the phosphate prodrug of PF-00835231, a protease inhibitor targeting the 3C-like protease of SARS-CoV-2. This phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of single ascending intravenous doses of lufotrelvir (continuous 24-hour infusion of 50, 150, 500, or 700 mg) versus placebo in healthy volunteers (2 interleaving cohorts: 1, n = 8; 2, n = 7). Each dosing period was separated by a washout interval (≥5 days). Treatment-emergent adverse events, PK, and biomarker concentrations were estimated from plasma/urine samples. Lufotrelvir was administered to 15 volunteers (mean [SD] age 39.7 [11.8] years). No serious adverse events, discontinuations, or deaths were reported. Mean maximum observed concentration of PF-00835231 (active moiety; 97.0 ng/mL to 1288 ng/mL) were observed between median time to maximum concentration of 14 to 16 hours after the start of the lufotrelvir infusion. Near-maximum plasma concentrations of PF-00835231 were observed ≈6 hours after infusion start and sustained until infusion end. PF-00835231 plasma concentrations declined rapidly after infusion end (mean terminal half-life: 500 mg, 2.0 hours; 700 mg, 1.7 hours). Approximately 9%-11% of the dose was recovered in urine as PF-00835231 across doses. A continuous, single-dose, 24-hour infusion of lufotrelvir (50-700 mg) was rapidly converted to PF-00835231 (active moiety), with dose-proportional PK exposures and no significant safety concerns. A daily, 24-hour continuous infusion of 270 to 350 mg is expected to maintain PF-00835231 concentration at steady state/above effective antiviral concentrations. Further studies exploring lufotrelvir efficacy in patients with coronavirus disease 2019 are ongoing.

Simulation of Remdesivir Pharmacokinetics and Its Drug Interactions.

PURPOSE: Remdesivir, a drug originally developed against Ebola virus, is currently recommended for patients hospitalized with coronavirus disease of 2019 (COVID-19). In spite of United States Food and Drug Administration's recent assent of remdesivir as the only approved agent for COVID-19, there is limited information available about the physicochemical, metabolism, transport, pharmacokinetic (PK), and drug-drug interaction (DDI) properties of this drug. The objective of this in silico simulation work was to simulate the biopharmaceutical and DDI behavior of remdesivir and characterize remdesivir PK properties in special populations which are highly affected by COVID-19. METHODS: The Spatial Data File format structures of remdesivir prodrug (GS-5734) and nucleoside core (GS-441524) were obtained from the PubChem database to upload into the GastroPlus software 9.8 version (Simulations Plus Inc., USA). The Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) Predictor and PKPlus modules of GastroPlus were used to simulate physicochemical and PK properties, respectively, in healthy and predisposed patients. Physiologically based pharmacokinetic (PBPK) modeling of GastroPlus was used to simulate different patient populations based on age, weight, liver function, and renal function status. Subsequently, these data were used in the Drug-Drug Interaction module to simulate drug interaction potential of remdesivir with other COVID-19 drug regimens and with agents used for comorbidities. RESULTS: Remdesivir nucleoside core (GS-441524) is more hydrophilic than the inactive prodrug (GS-5734) with nucleoside core demonstrating better water solubility. GS-5734, but not GS-441524, is predicted to be metabolized by CYP3A4. Remdesivir is bioavailable and its clearance is achieved through hepatic and renal routes. Differential effects of renal function, liver function, weight, or age were observed on the PK profile of remdesivir. DDI simulation study of remdesivir with perpetrator drugs for comorbidities indicate that carbamazepine, phenytoin, amiodarone, voriconazole, diltiazem, and verapamil have the potential for strong interactions with victim remdesivir, whereas agents used for COVID-19 treatment such as chloroquine and ritonavir can cause weak and strong interactions, respectively, with remdesivir. CONCLUSIONS: GS-5734 (inactive prodrug) appears to be a superior remdesivir derivative due to its hepatic stability, optimum hydrophilic/lipophilic balance, and disposition properties. Remdesivir disposition can potentially be affected by different physiological and pathological conditions, and by drug interactions from COVID-19 drug regimens and agents used for comorbidities.